We have convincingly shown that natural killer (NK) cells facilitate the pathogenesis of sepsis caused by cecal ligation and puncture (CLP). However, the mechanisms that contribute to NK cell-mediated pro-inflammatory activity during sepsis are poorly understood. Our recent studies indicate large numbers of CXCR3+ NK cells leave the spleen and enter the peritoneal cavity during CLP-induced sepsis. The CXCR3 ligands CXCL9 and CXCL10 are present at high concentrations during sepsis and CXCR3-deficient mice are resistant to CLP-induced physiologic dysfunction. Based on these observations, we hypothesize that CXCR3 signaling is critical for the recruitment and activation of NK cells and that the actions of CXCR3 are important in the pathogenesis of sepsis. The following specific aims will test these hypotheses.
Specific Aim 1 : To determine the importance of CXCR3 for NK cell migration and activation as well as its impact on the pathogenesis of CLP- induced sepsis. The expression of CXCR3 and markers of activation will be evaluated on NK cells at the primary site of infection and in remote tissues. Further studies will assess NK cell recruitment and activation in CXCR3-deficient mice and after blockade of CXCR3 with neutralizing antibodies. We will also determine the importance of CXCR3 in the pathogenesis of sublethal sepsis, sepsis-induced multi- organ dysfunction and septic shock.
Specific Aim 2. To determine the importance of CXCR3 ligands (CXCL9 and CXCL10) for NK cell recruitment and activation as well as their impact on the pathogenesis of CLP-induced sepsis. The cellular sources of CXCR3 ligands at the primary site of infection and remote tissues will be examined. NK cell migration and activation will be studied in CXCR3 ligand-deficient mice or after blockade of CXCR3 ligands using neutralizing antibodies. Physiological function, organ injury and systemic inflammation will be examined in CXCR3 ligand- deficient mice using models of sublethal sepsis, sepsis-induced multi-organ dysfunction and septic shock. We will also determine the ability of CXCR3 ligands to directly induce the sepsis syndrome in control mice or mice with sublethal sepsis.
Specific aim 3. Evaluation of factors that regulate the CXCR3 axis during CLP-induced sepsis. These studies will examine the contributions of NK cells to CXCR3 ligand production and the factors that regulate NK cell CXCR3 expression during sepsis. Although LPS-induced CXCL10 production by isolated macrophages is considered to be regulated by Trif-dependent signaling and require production of IFN?, we propose that NK cells will facilitate MyD88- dependent CXCL10 production through the production of IFN?. Studies are proposed in this application to address that assertion. Further studies will evaluate the importance of paracrine and autocrine mechanisms for NK cell CXCR3 activation and the factors that regulate CXCR3 expression by NK cells.

Public Health Relevance

We have convincingly shown that natural killer (NK) cells facilitate the pathogenesis of sepsis. The chemokine receptor CXCR3 is known to regulate NK cell functions in some disease models. Based on our recent research, we hypothesize that CXCR3 signaling is critical for the recruitment and activation of NK cells during sepsis and that blockade of CXCR3 will improve outcome in septic animals.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM066885-09
Application #
8292209
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Dunsmore, Sarah
Project Start
2003-07-01
Project End
2012-07-02
Budget Start
2012-07-01
Budget End
2012-07-02
Support Year
9
Fiscal Year
2012
Total Cost
$1
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Patil, Naeem K; Bohannon, Julia K; Sherwood, Edward R (2016) Immunotherapy: A promising approach to reverse sepsis-induced immunosuppression. Pharmacol Res 111:688-702
Patil, Naeem K; Luan, Liming; Bohannon, Julia K et al. (2016) IL-15 Superagonist Expands mCD8+ T, NK and NKT Cells after Burn Injury but Fails to Improve Outcome during Burn Wound Infection. PLoS One 11:e0148452
Guo, Yin; Luan, Liming; Rabacal, Whitney et al. (2015) IL-15 Superagonist-Mediated Immunotoxicity: Role of NK Cells and IFN-γ. J Immunol 195:2353-64
Hotchkiss, Richard S; Sherwood, Edward R (2015) Immunology. Getting sepsis therapy right. Science 347:1201-2
Herzig, Daniela S; Luan, Liming; Bohannon, Julia K et al. (2014) The role of CXCL10 in the pathogenesis of experimental septic shock. Crit Care 18:R113
Bohannon, Julia K; Hernandez, Antonio; Enkhbaatar, Perenlei et al. (2013) The immunobiology of toll-like receptor 4 agonists: from endotoxin tolerance to immunoadjuvants. Shock 40:451-62
Herzig, Daniela S; Driver, Brandon R; Fang, Geping et al. (2012) Regulation of lymphocyte trafficking by CXC chemokine receptor 3 during septic shock. Am J Respir Crit Care Med 185:291-300
Herzig, Daniela S; Guo, Yin; Fang, Geping et al. (2012) Therapeutic efficacy of CXCR3 blockade in an experimental model of severe sepsis. Crit Care 16:R168
Bohannon, Julia; Guo, Yin; Sherwood, Edward R (2012) The role of natural killer cells in the pathogenesis of sepsis: the ongoing enigma. Crit Care 16:185
Herzig, Daniela; Fang, Geping; Toliver-Kinsky, Tracy E et al. (2012) STAT1-deficient mice are resistant to cecal ligation and puncture-induced septic shock. Shock 38:395-402

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